Normal kidney function is critical for the maintenance of potassium homeostasis. The ability of the kidney to maintain potassium homeostasis depends on several factors, including the normal production of aldosterone, sodium delivery to the distal nephron, and adequate sodium-potassium exchange in the cortical collecting duct (Palmer, B. F., N. Engl. J. Med. 2004, 351:585-92). Of these factors, aldosterone production and action is closely regulated by the renin-angiotensin-aldosterone system (RAAS), a cornerstone of the regulatory components controlling blood pressure, blood volume and cardiovascular function. RAAS inhibition, designed to limit aldosterone production and function, is therefore an important treatment strategy for hypertension, diabetes, chronic kidney disease and heart failure. Several studies have demonstrated the renal protective effects of angiotensin receptor blockers (ARBs) such as losartan or irbesartan (Brenner, B. M. et al., N. Engl. J. Med. 2001, 345:861-869; de Zeeuw, D. et al. Kidney Intl. 2004, 65:2309-2320; Miao, Y. et al., Diabetologia 2010; Lewis, E. J. et al., N. Engl. J. Med. 2001, 345:851-860; Atkins, R. C. et al., Am. J. Kidney Dis. 2005, 45:281-287), while studies using dual blockade of the RAAS with an aldosterone antagonist (spironolactone or eplerenone), added to either angiotensin converting enzyme inhibitor (ACEI) or ARB therapy, were shown to substantially reduce cardiovascular endpoints in heart failure or post-myocardial infarction patients (Pitt, B. et al., N. Engl. J. Med. 1999, 341:709-717; Pitt, B., Molecular & Cellular Endocrinol. 2004, 217:53-58; Zannad, F. et al., European J. Heart Failure 2010).
Despite the demonstrated clinical benefits of RAAS inhibitors, the fundamental mode of action of the drugs disturbs the exchange of sodium for potassium in the kidney tubule. As a result, potassium retention can precipitate hyperkalemia, defined as a serum potassium value >5.0 mEq/L. This is particularly problematic in patients with reduced renal function resulting from chronic kidney disease and common co-morbidities such as hypertension, diabetes and heart failure. In this situation, the combination of RAAS inhibition and reduced renal function can aggravate the nascent positive potassium balance and trigger a hyperkalemic event. The discontinuation or reduction in the dose of RAAS inhibitors is a common intervention for patients taking RAAS inhibitors who show abnormally elevated serum potassium levels, which deprives patients of the benefits of RAAS inhibitors. Thus, there is a need to control blood pressure in patients and treat hyperkalemia.